Luminescent Molecular Sensors For The Selective Detection Of Neurodegenerative Disease Protein Pathology In Csf

Alzheimer's disease (AD) is a leading cause of death worldwide for which we have no clinically useful diagnostic tools, nor do we have a treatment. The disease is characterized by the misfolding and aggregation of the amyloid beta (Aβ) and tau proteins that cause neuronal damage. Neuronal loss occurs decades prior to the onset of symptoms, making the pre-symptomatic stage an ideal target window for detection and treatment. Research has shown that levels of proteins and small molecules in the cerebrospinal fluid (CSF) can be used as biomarkers for detecting and monitoring certain neurodegeneration processes, such as cognitive decline. Changes in the levels of Aβ and tau in the CSF are also being investigated as AD biomarkers. Herein we have characterized two small phenylene ethynylene (PE)-based conjugated polyelectrolytes, anionic OPE1, and cationic OPE2, as novel sensors for Aβ and tau aggregates in the CSF. We have previously demonstrated the efficiency of these OPEs for the selective in vitro and ex vivo detection of amyloid protein aggregates. In this work, we tested the selective sensing of OPEs for amyloid protein aggregates in the CSF. Aggregates of model proteins, hen egg white lysozyme, bovine insulin, and disease-relevant proteins, Aβ40, PHF6 (VQIVY), and human-derived tau oligomers, were added to CSF pooled from healthy human subjects and sensor selectively, limits of detection and sensitivity were quantified using a combination of techniques, including fluorescence measurements, reverse phase-HPLC, and transmission electron microscopy. Our results indicate that the larger, cationic OPE2 molecule has high selectivity for the amyloids in CSF over its anionic analog. The selective sensing of OPEs was validated for its use to detect pathological Aβ and tau biomarkers in CSF, which could lead to early detection and diagnosis of AD.